Serotonin in the Modulation of Neural Plasticity and Networks. Implications for Neurodevelopmental...

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widely distributed transmitter in the brain (Dahlstrom and Fuxe,

5-HT is involved in basic morphogenetic activities during brain

processes, which supports competent social functioning, has

neural circuits to process and refine information. Thus, identifi-Considerable evidence links dysfunction of 5-HT transmission

to neurodevelopmental and subsequent psychiatric disorders

characterized by compromised function of the so-called social

the brain 5-HT system and then discuss how 5-HT shapes brain

networks during development and modulates a spectrum of

essential neuronal functions. We will consider the current under-brain (Blakemore, 2008; Frith and Frith, 2012). The social brain

is a construct comprising representations of internal somatic

standing of how 5-HT receptor-mediated molecular mecha-

nisms contribute to neuronal development, synapse formationdevelopment and in the life-spanning adaptive capacity of the

brain, including modulation of neural cell proliferation, migration

and differentiation as well as neurite outgrowth, axonal guid-

ance, synaptogenesis, and efficiency of transsynaptic signaling

(for review, Azmitia and Whitaker-Azmitia, 1997; Daubert and

Condron, 2010; Gaspar et al., 2003).

cation of genetic variation affecting molecules essential for the

formation, specification, and function of excitatory and inhibitory

synapses is expanding research efforts in neurodevelopmental

disorders characterized by deficits in attention, motivation,

cognition, and emotion.

Here, we will first describe selected fundamental features of1964; Steinbusch, 1981). 5-HT signaling pathways integrate

not only basic physiology, but also essential brain functions,

including sensory processing, cognitive control, emotion regula-

tion, autonomic responses, and motor activity in an overarching

fashion. Vice versa, it is a target of many physiologic regulators,

including modulators of gene transcription, neurotrophic pep-

tides, and steroids as well as psychotropic therapeutics, which

impact the formation and activity of 5-HT subsystems.

Brain function is ultimately contingent on a specific patterning

of connections between distinct populations of neurons and the

establishment of functional neural circuits. The strength of

synaptic signals is continuously modified by sensory input,

event-related neural activity and experience, adaptive pro-

cesses commonly referred to as synaptic plasticity. The molec-

ular, cellular and circuitry changes associated with synaptic

plasticity are believed to moderate higher-order brain tasks,

such as social cognition and emotional learning and memory.

recently been associated with activity in distinct neural circuits,

including networks involved in imitation, imitative learning, social

cognition, and communication skills (Amodio and Frith, 2006;

Carr et al., 2003). Deficits in 5-HT-moderated synaptic signaling

resulting in impairments of these network processes fundamen-

tally impact pathophysiology and long-term outcome of neuro-

developmental disorders comprising a spectrum of diseases

ranging from schizophrenic psychoses to autism spectrum and

attention-deficit/hyperactivity disorders.

In addition to the role in synapse formation and network

construction during development, increasing evidence impli-

cates 5-HT in the regulation of cell adhesion molecules critically

involved in the plasticity of the developing and adult brain (Dalva

et al., 2007; Yamagata et al., 2003). These synaptic adhesion

molecules are principal components of the molecular machinery

that connects pre- and postsynaptic neurons, facilitates trans-

mission, controls synaptic plasticity, and empowers intersectingReview

Serotonin in the Modulationof Neural Plasticity and NetImplications for Neurodeve

Klaus-Peter Lesch1,2,* and Jonas Waider11Division of Molecular Psychiatry, Laboratory of Translational NeurosPsychosomatics and Psychotherapy, University of Wurzburg, 970802Department of Neuroscience, School of Mental Health and Neurosc*Correspondence: [email protected]://dx.doi.org/10.1016/j.neuron.2012.09.013

Serotonin (5-HT) shapes brain networks during deveneuronal functions ranging from perception and cogbrain. Deficits in 5-HT-moderated synaptic signalingterm outcome of neurodevelopmental disorders. Ouof circuit configuration influences social cognition ainsight into the molecular and cellular mechanisms odiscuss emerging concepts as to howdefects in synapfindings regarding 5-HTs role in brain development aiological basis of neurodevelopmental disorders.

IntroductionSerotonin (5-hydroxtryptamine, 5-HT), a phylogenetically

ancient signaling molecule (Hay-Schmidt, 2000), is the mostorks:opmental Disorders

ience, ADHD Clinical Research Network, Department of Psychiatry,urzburg, Germanynce, Maastricht University, 6211 LK Maastricht, The Netherlands

pment and modulates a wide spectrum of essentialitive appraisal to emotional responses in the matureundamentally impact the pathophysiology and long-understanding of how 5-HT-dependent modulationd emotional learning has been enhanced by recentsynapse formation and plasticity. In this review, weic plasticity impact our biosocial brain and how recentd function provide insight into the cellular and phys-

states, interpersonal knowledge, and motivations as well as

developmentally chiseled procedures used to decode and

encode the self relative to other people. This complex set ofNeuron 76, October 4, 2012 2012 Elsevier Inc. 175

Neuronand plasticity, and network connectivity related to social cogni-

tion and emotional learning. We explicitly focus on 5-HTs

capacity to orchestrate activities and interactions of other trans-

mitter systems by modifying the repertoire of molecules critically

involved in the remodeling of transsynaptic signaling, high-

lighting a selection of key players and newly discovered but

paradigmatic mechanisms. This overview is not meant to be

exhaustive but will touch upon emerging concepts of how defi-

cits in 5-HT-moderated synaptic signaling contribute to the path-

ophysiology of neurodevelopmental disorders.

Structural and Functional SubsystemsThe mammalian brain 5-HT system originates from the raphe

DR(B6, B7)HippocampusFrontal cortex

Olfactory bulb

MR(B5, B8)

Hypothalamus

ThalamusMFB

Striatum

N. accumbensAmygdala B9located in the midline of the rhombencephalon and in the retic-

ular formation, where 5-HT neurons are clustered into nine nuclei

numbered B1-9 on a rostrocaudal axis (Figure 1; Azmitia and

Whitaker-Azmitia, 1997; Dahlstrom and Fuxe, 1964). These clus-

ters are subdivided into rostral and caudal sections with the

rostral subdivision comprising the caudal linear nucleus (CLi),

the dorsal raphe nucleus (DR: B6, B7) and the median raphe

nucleus (MR: B9, B8, and B5). 5-HT neurons from the rostral

subdivision project primarily to the forebrain where the extensive

collateralization of their terminals densely innervate virtually all

regions (Calizo et al., 2011; Hensler, 2006; Hornung et al.,

1990). A stringent topographical organization of two classes of

fine and beaded fibers (termed D and M fibers, respectively)

define distinct patterns of termination modulating specified

arrays of neurons in the cortex, striatum, hippocampus, and

amygdala (Figure 2), thus influencing sensory processing, cogni-

tion, emotional states, circadian rhythms, food intake, and repro-

duction. The caudal portion, which projects mainly to the spinal

cord and cerebellum, consists of nuclei termed as raphe pallidus

(B1), raphe obscurus (B2), and raphe magnus (B3) is involved in

motor activity, pain control, and regulation of the autonomic

nervous system. Here, the focus will be on the modulatory func-

tion of the rostral subdivisions and the DR in particular.

Based on cellular morphology, expression of other transmit-

ters, afferent and efferent connections and functional properties,

the circumscribed rap

distinct 5-HT subsyste

by transcriptional re

factors that induce e

the Lim homeodomai

Lmx1b and Pet1, resp

et al., 2011). Pet1 is on

specification (Jacobse

while Lmx1b represe

expression cascade r

of all 5-HT neurons i

several secreted pos

growth factors (Fgf4, F

tically control cell fat

(Cordes, 2005). Beyon

action, the role of

posttranscriptional rep

tional regulation are in

(see below).

The 5-HT transporte

display transient and

development (Manso

2001). For receptors, e

expression patterns ar

176 Neuron 76, October 4, 2012 2012 Elsevier Inc.., 2009; Lesch et al., 2012a). Even within

he complex, morphogenetic programs in

ms in rodents are differentially controlled

gulators (Cordes, 2005). Transcription

xpression of 5-HT markers encompass

n and ETS domain transcription factor,

ectively (Hendricks et al., 1999; Kiyasova

e of the critical regulators of 5-HT system

n et al., 2011; Liu and Deneris, 2011),Cerebellum

MidbrainB1

B2

B3

B4

Figure 1. Rodent Brain 5-HT System5-HT neuron clusters are organized in the nineraphe nuclei, B1B9. The more caudal nuclei (B1B3) in the medulla project axons to the spinal cordand the periphery, whereas the more rostral raphenuclei contain the principal dorsal raphe group (B6and B7; depicted in yellow) and the median raphegroup (B5 and B8; depicted in green), whichproject to different but overlapping brain areas.DR, dorsal raphe nucleus; MFB, medial frontalbundle; MR, median raphe nucleus.

5-HT neurons of the DR are topographi-

cally grouped into six cell clusters

comprising the rostral, ventral, dorsal,

lateral, caudal, and interfascicular parts

of the DR (Calizo et al., 2011; Hensler,

2006; Waselus et al., 2006). In addition

to 5-HT cells, neurons transmitting

glutamate, GABA, dopamine, nitric oxide,

and numerous neuropeptides (e.g., neuropeptide Y, galanin,

somatostatin, thyrotropin-releasing hormone) were identified

(Fu et al., 2010). Multiple brain regions feed back to the DR,

utilizing a wide range of transmitters including glutamate, acetyl-

choline, GABA, norepinephrine, or neuropeptides.

Knowledge of themolecular mechanisms regulating the devel-

opment of 5-HT system remains limited. The regulation of the

proliferation, differentiation, maintenance and survival of 5-HT

neurons engage many signaling molecules, including inducers

of gene transcription, neurotrophic peptides, and steroids acting

in concert or in cascade. Whether intrinsic neuronal, maternal or

placental 5-HT is required as facilitator of 5-HT circuitry

development remains controversial (Daubert and Condron,

2010; Gutknecht et al

Reviewnts a major determinant in the gene

esulting in the phenotypic determination

n brain (Song et al., 2011). Additionally,

itional markers, including the fibroblast

gf8) and Sonic hedgehog (Shh) synergis-

e and the generation of 5-HT neurons

d transcription initiation and neurotrophin

mRNA elongation, microRNA-mediated

ression and other mechanisms of transla-

creasingly attracting systematic scrutiny

r (5-HTT) and several 5-HT receptors also

variable patterns of expression during

ur-Robaey et al., 1998; Persico et al.,

nzymes, and transporters, developmental

e highly plastic, with prenatal exposure to

Neuron$

Prefrontalcortex

Dorsalstriatum

TAN

Review5-HT functionmodifying compounds or toxins causing long-term

expression changes persisting into adulthood. Moreover,

genetic variation in key players of 5-HT system development

has been shown to affect the 5-HTs neuromodulatory capacity

with consequences for the cognition-emotion continuum (Gross

and Hen, 2004; Pessoa, 2008).

Multiplicity of Signaling PathwaysSerotonergic input into neural networks implicated in sensory

processing, cognitive control, emotion regulation, autonomic

responses, and motor action is composed of two distinct 5-HT

systems differing in their topographic organization, electrophys-

iological signature, morphology, and sensitivity to neurotoxins

and psychoactive compounds (Figure 2). There are at least

fourteen structurally and pharmacologically divergent 5-HT

receptors (Barnes and Sharp, 1999; Millan et al., 2008). Beyond

isoform diversity, alternative splicing of some subtypes (e.g.,

BLA

LA

Amygdala

MSN

Figure 2. Modulation of Glutamate- and GABA-Mediated TransmissionFor example, excitatory transmission within hippocampal areas CA13 is largely blayer II stellate cells in the entorhinal cortex, the mossy fiber axons originating fropyramidal cells. The synaptic communication of each of these pathways ismodulaand strength of the connection. 5-HT1B receptors, located on axon terminals fromto neighboring pyramidal neurons and to local interneurons. The release of GABA fand inhibited by 5-HT1A receptors. 5-HT and GABAB receptors, respectively, innosum moleculare. In the dentate gyrus, 5-HT3 receptors stimulate GABA releasemediated currents acting both pre- and postsynaptically; 5-HT and GABAB recSeveral 5-HT receptors are also expressed by cells of dorsal striatum includingneurons (TAN). In other brain regions distinct 5-HT receptors are required for difimplicated in regulating short-term plasticity. Presynaptically expressed 5-HT recand they are be distributed in a target-specific manner, such that synaptic input frits postsynaptic targets. 5-HT signaling specifies a mechanism for synaptic specithe strength and timing of network activity within pyramidal cells, other principleDorsalhippocampus

CA1

DG

5-HT projections

Thin, varicose axon system (D fibers)Basket axon system (M fibers)5-HT4) and RNA editing of the 5-HT2C receptor add to the diver-

sity of the 5-HT receptor family. It continues to be a daunting task

to dissect the physiological impact of individual receptors,

design selective ligands to target specific subtypes, and deter-

mine potential therapeutic value of novel compounds. Molecular

characterization of 5-HT receptor subtypes, functional mapping

of transcriptional control regions, and the modeling of 5-HT

receptor gene function in genetically modified mice has yielded

valuable information regarding respective roles of 5-HT recep-

tors and other components of serotonergic signaling pathways

in brain development, synaptic plasticity, and behavior.

The well-characterized 5-HT1A subtype is a G protein-

coupled receptor (GCPR) that operates both pre- and postsyn-

aptically (Figure 2). Somatodendritic 5-HT1A autoreceptors are

predominantly located on the soma and dendrites of neurons

in the raphe complex and its activation by 5-HT or 5-HT1A

agonists induces hyperpolarization, decreases the firing rate of

DR

MR

CA3

PyramidalPV

GABAergic neurons neuron Non-PV

Midbrain5-HT1A

5-HT35-HT2C5-HT2A5-HT1B

5-HT4

by 5-HT in the Cortex, Striatum, Hippocampus, and Amygdalaased on three glutamatergic pathways: the perforant path formed by axons ofm the dentate gyrus granule cells, and the recurrent axon collaterals of CA13ted by 5-HT receptors that fine-tune synaptic signal by affecting both the timingpyramidal neurons and on their recurrent collaterals, inhibit glutamate release

romCA1 inhibitory interneurons is stimulated by 5-HT2 and by 5-HT3 receptorscrease and decrease T-type Ca2+ current on interneurons from stratum lacu-from interneurons. In CA3 pyramidal neurons, 5-HT inhibits GABAB receptor-eptors cooperate in increasing a hyperpolarizing outward potassium current.the medium-sized spiny neurons (MSN), the tonically active cholinergic inter-ferent forms of pre- and postsynaptic long-term plasticity and also have beeneptors affect the timing of action potentials elicited in the postsynaptic targetom one presynaptic neuron can be modulated by different receptors at each ofalization of glutamatergic and GABAergic transmission and thus contributes toneurons and interneurons.

Neuron 76, October 4, 2012 2012 Elsevier Inc. 177

Neuron5-HT neurons, and subsequently reduces the synthesis, turn-

over, and release of 5-HT from axon terminals in projection areas

(Gutknecht et al., 2012; Lesch, 2005). Postsynaptic 5-HT1A

receptors are widely distributed in forebrain regions, notably in

the cortex, hippocampus, septum, amygdala, and hypothal-

amus. Hippocampal heteroreceptorsmediate neuronal inhibition

by coupling to the G protein-gated inward rectifying potassium

channel subunit-2 (GIRK2). The metabotropic and ion channel-

regulating actions of the 5-HT1A receptor are implicated in

learning and memory (Ogren et al., 2008) and in the pathophys-

iology and treatment response of a wide range of disorders

characterized by cognitive and emotional dysregulation (Gross

and Hen, 2004; Gross et al., 2002). Chronic stress mediated by

glucocorticoids has been reported to result in downregulation

of 5-HT1A receptors in the hippocampus in animal models

(Meijer et al., 1998). In line with this notion, evidence is accumu-

lating that functional variation in the 5-HT1A gene (HTR1A) is

associated with personality traits of negative emotionality (Stro-

bel et al., 2003) as well as the etiology of disorders of the anxio-

depressive spectrum (Rothe et al., 2004; for review, Albert, 2012;

Le Francois et al., 2008).

By associating with multiple GPCR interacting proteins, two

other metabotropic receptors, 5-HT2A and 5-HT2C, impact

a wide range of signal transduction pathways (Bockaert et al.,

2010). Both 5-HT2A and 5-HT2C receptor-agonist complexes

activate phospholipase C (PLC). 5-HT2C is critically involved in

the regulation of synaptic plasticity, since it initiates the phos-

phoinositol second messenger cascade by producing inositol

triphosphate (IP3) and diacylglycerol (DAG), which ultimately

leads to opening L-type Ca2+ channels following release of

calcium stores. Moreover, the protein phosphatase and tensin

homolog (PTEN) binds to 5-HT2C, and disruption of 5-HT2C/

PTEN complexes can alter neuronal activity (Bockaert et al.,

2010). There is evidence that the 5-HT2C receptor also interacts

with proteins containing PSD-95-disc large-zonula occludens

(PDZ) domains, and association of 5-HT2C receptors with PDZ

proteins affects both receptor desensitization and internaliza-

tion, depending on the type of the PDZ protein associated with

the receptor (Becamel et al., 2004). The spatiotemporal diversity

of these interactions highlights the wide range of 5-HT-mediated

adaptive plasticity at the synaptic level.

5-HT1A and 5-HT2A/2C receptors can be expressed in

both excitatory principal neurons and inhibitory interneurons

(Figure 2), which renders the net outcome of the neuromodula-

tory action of 5-HT on circuit activity dependent on multiple

factors (e.g., local 5-HT concentration, receptor ratio and intra-

cellular coupling) (Cruz et al., 2004; de Almeida and Mengod,

2008; Llado-Pelfort et al., 2012; Puig et al., 2005). On glutamater-

gic pyramidal neurons, 5-HT1A receptors are distributed

diffusely and at relatively high density over the perikaryon,

dendrites, and synaptic spines, whereas 5-HT2A/2C receptors

are localized to the proximal dendritic shafts of glutamatergic

pyramidal neurons, and more diffusely on synaptic spines, inclose association with glutamate receptors (de Almeida and

Mengod, 2007; Gonzalez-Maeso et al., 2008). In addition, 5-

HT1A and 5-HT2A/2C receptors are found on terminals and

perikarya of GABAergic interneurons, respectively (de Almeida

and Mengod, 2008; Navailles and De Deurwaerdere, 2011).

178 Neuron 76, October 4, 2012 2012 Elsevier Inc.5-HT1A activation decreases N-methyl D-aspartate (NMDA)

receptor-mediated currents in pyramidal neurons of the pre-

frontal cortex (PFC) through reduction of ERK1/2 activity, which

leads to a decrease in microtubule-associated protein-2 (MAP2)

phosphorylation, MAP2-microtubule interaction and microtu-

bule stability involved in clustering the NMDA receptor-2B

subunit (Yuen et al., 2005). In contrast, 5-HT2A/2C activation

increases NMDA receptor-mediated currents by activating the

ERK1/2 pathway via the b-arrestin/Src/dynamin cascade, thus

counteracting the effects of 5-HT1A activation in decreasing

NMDA receptor-mediated currents (Yuen et al., 2008). Thus,

5-HT1A- and 5-HT2A/2C-activated signaling pathways appear

to converge at antagonistic actions on ERK1/2.

Somatosensory Cortex DevelopmentConverging lines of evidence suggest differential roles of 5-HT in

the developing and adult brain. During specific time windows of

embryogenesis, 5-HT in concert with other transmitters regu-

lates brain cytoarchitecture and nodal connectivity by modu-

lating a wide variety of developmental processes, including

neural progenitor cell proliferation, migration and differentiation,

maturation of postmitotic neurons and apoptosis (Erzurumlu and

Gaspar, 2012, and references therein). Environmental factors

that alter serotonergic modulation during development or varia-

tion in genes involved in 5-HT signaling can cause disorders

associated with defective innervation, circuit formation, and

network connectivity.

Numerous investigations of 5-HTs participation in neocortical

development and plasticity focused on the rodent visual and

particularly the somatosensory cortex (SSC), due to its one-to-

one correspondence between the sensory system and its

cortical projection area (Figure 3). Here, to provide an example

of how the serotonergic system can impact cortical develop-

ment, we consider the formation of the SSC and its activity-

dependent plasticity. The pronounced growth of the cortex

during development coincides with progressive serotonergic

innervation. During this period, incoming 5-HT neuron terminals

begin to establish synaptic interactions with target neurons and

to elaborate a profuse branching pattern, matching the transient

barrel-like expression and distribution of 5-HT, 5-HT1B, and

5-HT2A receptors as well as the 5-HTT, which regulates extra-

cellular 5-HT levels by mediating high-affinity reuptake, in

early-postnatal primary SSC (Mansour-Robaey et al., 1998).

The barrel-like 5-HT pattern in layer 4 of the SSC stems from

5-HT uptake and vesicular storage in thalamocortical neurons,

transiently expressing both 5-HTT and the vesicular monoamine

transporter-2 (VMAT2) despite their ultimate glutamatergic

specification.

5-HT dysregulation profoundly disturbs formation of the SSC

with altered cytoarchitecture of cortical layer 4, the layer

that contains synapses between thalamocortical terminals and

their postsynaptic target neurons (Persico et al., 2001). 5-Htt

knockout mice display a lack of characteristic barrel-like clus-

Reviewtering of layer 4 neurons in the SSC, despite relatively preserved

trigeminal and thalamic patterns (other phenotypes of 5-Htt-

deficient mice are described in Figure 4). 5-HT synthesis inhibi-

tion within a narrow early postnatal time window (P0P4)

completely rescues formation of SSC barrel fields, indicating

123

4

5

6

123

4

5

6

GLU

5-HTRaphe

NMDAAMPA

5-HT2A

TCA

GLU

5-HT1B

5-HTT

GLU

5-HTRaphe

AMPA

5-HT2A

5-HTTAMPA

TCA

GLU

GLU

5-HTRaphe

NMDAAMPA

5-HT2A

TCA

GLU

5-HT1B 5-HT5-HT 5-HT

Adult cross-modalsynaptic plasticity

S1 cortex

5-HTneuronterminals

5-HT transporterinactivation

LTP

Layer 4barrel

123

4

5

6

CA B

Barrel cortex

Neonataldevelopment

GanglionGasseri

V sensory nerveth

Ventrobasalthalamus

Figure 3. Development and Plasticity of the Somatosensory Cortex(A) The rodent somatosensory cortex (SSC) is characterized by one-to-one correspondence between the sensory system and its cortical projection area. Eachwhisker on the rodent snout is somatotopically represented in the trigeminal nucleus (termed barrelette), ventro-postero-medial thalamus (barreloid) and primarysomatosensory cortex (barrel). Cortical barrels encompass a hollow center with abundant thalamocortical terminals and few granule cells in layer 4, surroundedby a ring of dense granule cells separated by septal spaces. Thalamocortical afferents (TCA) from the ventrobasal thalamic nucleus are distributed somato-topically perinatally and play an instructive role in subsequent cortical barrel field formation. Afferents-instructed barrel formation is representative of theperipheral-to-central maturation cascade, with barrelettes forming prenatally, barreloids approximately at birth and barrels around P4. Peripheral sensory input,e.g., via whisker-mediated stimuli, is critical to the organization of the barrel field during an early postnatal critical period (i.e., P0P4).(B) 5-Htt knockout mice display a lack of characteristic barrel-like clustering of layer 4 neurons in the SSC, despite relatively preserved trigeminal and thalamicpatterns. Cell bodies as well as terminals, typically more dense in barrel septa, appear homogeneously distributed in layer 4 of adult brains. Excessiveconcentrations of extracellular 5-HT are deleterious to SSC development suggesting that transient 5-HTT expression and its permissive action in thalamocorticalneurons is required for normal barrel pattern formation in neonatal rodents, by maintaining extracellular 5-HT concentrations below a critical threshold. 5-HT1Breceptors are the direct targets of excess 5-HT.While activation of 5-HT1B inhibits neurotransmitter release, specifically reducing excitatory neurotransmission inthalamocortical regions of somatosensory systems, 5-HT1B receptors act as regulators of thalamocortical development through inhibition of glutamate (GLU)release. Since normal synaptic density of 5-HT neuron terminal in SSC layer 4 of 5-Htt knockout mice is maintained, it is likely that 5-HT affects SSC cy-toarchitecture by promoting dendritic growth toward the barrel hollows, as well as by modulating cytokinetic movements of cortical granule cells.(C) 5-HT also moderates activity-dependent cross-modal plasticity, a procedure of cortical restructuring to compensate for the loss of one sensory systemwith other intact modalities in the mature brain, specifically among the SSC and visual system. Increases in extracellular 5-HT in the rodent SSC followingvisual deprivation enables synaptic strengthening at layer 4 to layer 2/3 synapses in response to whisker-dependent stimulation of neural activity. Theenhanced transsynaptic signaling efficiency is achieved by insertion of AMPA receptors into synapses at postsynaptic neurons through activation of the5-HT2A/2C-dependent ERK1/2 signaling pathways and increased phosphorylation of AMPA receptor subunit GluR1, thus leading to sharpening andfine-tuning of the functional whisker-barrel map at layer 4-2/3 at an age when natural whisker experience fails to induce synaptic GluR1 delivery. LTP, long-termpotentiation.


Neuron

Review

incth

Neuronet al., 2010) and that intra- and extra-uterinematernal signals can synergisticallyand psychiatric disorders (Bartolomucci et al., 2010; Carola et al., 2008; Leshaploinsufficiency of 5-HT system interacting genes, such as Bdnf or Pten, furthat excessive concentrations of extracellular 5-HT are delete-

rious to SSC development. Thus, by maintaining extracellular

5-HT concentrations below a critical threshold, transient 5-HTT

expression and its permissive action in thalamocortical neurons

is required for normal barrel pattern formation in neonatal

rodents. Converging lines of evidence support 5-HTB receptors

as direct targets of excess 5-HT. Since activation of 5-HT1B

inhibits transmitter release, specifically reducing excitatory

transmission in thalamocortical regions of both the visual and

somatosensory systems, hypotheses based on modulation

of electrophysiological activity view 5-HT1B receptors as

regulators of thalamocortical development through inhibition of

glutamate release (Salichon et al., 2001). Since normal synaptic

density of 5-HT neuron terminal in SSC layer 4 of 5-Htt knockout

mice ismaintained, it is likely that 5-HT affects SSC cytoarchitec-

ture by promoting dendritic growth toward the barrel hollows, as

well as by modulating cytokinetic movements of cortical granule

cells. In total, the interplay of 5-HT synthesis, release, uptake and

degradation by raphe-cortical and thalamocortical axon arbors

at target neurons and subsequent differential activation of me-

tabotropic 5-HT1B receptors plays a critical role in the formation

of sensory and potentially other cortical fields.

Activity-Dependent Cortical PlasticityNeuronal plasticity in the mature cortex is regulated by cognitive

and emotional functions such as processes related to percep-

tion, attention, motivation, associative and emotional learning,

and memory (Holtmaat and Svoboda, 2009). By innervating

regions implicated in higher-order brain function, the 5-HT

sociability in a sex-specific manner (Page et al., 2009; Ren-Patterson et al., 20behavior underscores the view that environmental influences can persistently reminformative for the dissection of the molecular and neural mechanisms of epiginteractions may constitute neural mechanisms for (epi)genetic vulnerability towa

180 Neuron 76, October 4, 2012 2012 Elsevier Inc.Figure 4. 5-HT Transporter as a MasterController of Brain 5-HT System FunctionTargeted mutations resulting in reduced orcompletely inactivated 5-Htt (Sert, Slc6a4) func-tion in mice have led to the identification of morethan 50 different phenotypic changes, rangingfrom increased anxiety and stress-related behav-iors to gut dysfunction, bone weakness, and late-onset obesity with metabolic syndrome (Murphyand Lesch, 2008). These multiple effects, whichmay be amplified by gene-by-environment (G3E)and gene-by-gene (G3G) interactions, are pri-marily attributable to altered intracellular andextracellular 5-HT concentrations during sensitiveperiods in development and adulthood (Ansorgeet al., 2004). In addition, the 5-Htt knockout mouseprovides a model to study the impact of geneticmechanisms on development and plasticity ofthe brain including regionalization of the cortexand its connectivity to subcortical structures(Nietzer et al., 2011; Persico et al., 2001; Salichonet al., 2001; Wellman et al., 2007). Furthermore,evidence indicates that 5-HT-dependent tran-scriptional programming of maternal behavior haslong-lasting consequences on (social) cognitiveand emotional behavior in the offspring (Barr et al.,2004; Bennett et al., 2002; Canli et al., 2006;Jansen et al., 2011; Kloke et al., 2011; Lewejohann

duce enduring plastic changes in neurocircuits involved in neurodevelopmentalh, 2011; van den Hove et al., 2011). Inactivation of 5-Htt in interaction wither aggravates deficits in brain development as well as emotional behavior and

Reviewsystem plays a predominant role in the modulation of these

functions. Although dynamic cortical reorganization of areas

involved in cognition and emotion is critical for this adaptation

and the enhancement of neural plasticity in response to activa-

tion of the raphe 5-HT system is well established (Bennett-Clarke

et al., 1996; Inaba et al., 2009; Jones et al., 2009; Kim et al., 2006;

Maya Vetencourt et al., 2008; Normann and Clark, 2005), the

underlying molecular, synaptic, and circuit mechanisms are

only beginning to be adequately understood.

Raphe 5-HT neurons orchestrate cortical reorganization

among different sensory and effector systems via modification

of transsynaptic signaling efficiency at excitatory synapses. In

the mammalian brain, the majority of excitatory synapses use

glutamate as transmitter. Glutamate activates both ionotropic

(AMPA-, kainate-, and NMDA-type) receptors and metabotropic

(mGluR) receptors. Fast glutamatergic transmission is primarily

mediated by AMPA receptors, while mGluRs modulate the

response to ionotropic glutamate receptors and that of other

transmitters, including dopamine, 5-HT, and GABA (De Blasi

et al., 2001). The principal cellular mechanism for 5-HT to impact

synaptic plasticity is long-term potentiation (LTP), an enduring

increase in synaptic transmission efficiency that has been

proposed to represent the physiological basis of learning and

memory. Synaptic delivery and insertion of AMPA receptors

mediated by lateral diffusion from extrasynaptic sites appears

central to the induction of postsynaptic LTP (Bredt and Nicoll,

2003; Malinow and Malenka, 2002; Figure 5). Detailed knowl-

edge about the molecular mechanisms underlying 5-HT-medi-

ated plasticity is now emerging and it has become clear that

06; Ren-Patterson et al., 2005). This (epi)genetic programming of emotionalodel neuronal units during early development, rendering 5-Htt modified miceenetic programming at the neurodevelopmental-behavioral interface. Theserd, or resilience against disease.

Neuronserotonergic signaling modulates intracellular pathways in-

volved in synaptic AMPA receptor delivery. Activation of the

5-HT2A-dependent ERK1/2 pathways enhances transsynaptic

signaling efficiency via insertion of AMPA receptors into

synapses at postsynaptic neurons (Makino and Malinow, 2009)

and increased phosphorylation of AMPA receptor subunit

GluR1 at Ser845 (Derkach et al., 2007).

5-HT also moderates cross-modal plasticity, a procedure of

cortical restructuring to compensate for the loss of one sensory

system with other intact modalities in the mature brain, specifi-

cally among the SSC and visual system. Increases in extracel-

lular 5-HT in exclusively the rodent barrel cortex following visual

deprivation enables synaptic strengthening at layer 4 to layer 2/3

synapses in response to whisker-dependent stimulation of

neural activity (Jitsuki et al., 2011). The enhanced transsynaptic

signaling efficiency due to AMPA receptor addition to synapses

leads to sharpening and fine-tuning of the functional whisker-

barrel map at layer 4-2/3 at an age when natural whisker experi-

ence fails to induces synaptic GluR1 delivery. Taken together,

sensory deprivation of onemodality increases 5-HT release in re-

maining modalities, which in turn modulates intracellular

signaling pathways involved in AMPA receptor delivery facili-

tates GluR1-subunit dependent synaptic strengthening, and

enables cortical reorganization, thus improving whisker barrel-

dependent sensory function.

Powering Synaptic Plasticity: Molecules for Bridging theCleftWhile enhancement of plasticity in response to activation of the

5-HT system has been well-established by electrophysiological

approaches, the underlying molecular mechanisms are now un-

folding. Synaptic adhesion molecules and secreted signaling

proteins regulate distinct aspects of neuronal circuitry formation

and function. Coordinated actions of a large diversity of molec-

ular signals contribute to the specification and differentiation of

synaptic connections in the developing and mature brain.

Evidence has been accumulating that 5-HT signaling modulates

these adhesion complexes. In this section, we provide a brief

overview of synaptic adhesion molecules and their functions.

Establishment of functional circuits and tight regulation of

connectivity require precision and specificity of neural wiring at

the laminar, cellular, subcellular, and synaptic levels (Williams

et al., 2010a). Transmembrane adhesion proteins are essential

constituents of synapses that play fundamental roles in building

and maintaining synaptic structure during development and

serve diverse purposes in synaptic plasticity of the brain

throughout the entire life span (Benson et al., 2000; Dalva

et al., 2007; Murase and Schuman, 1999; Yamagata et al.,

2003). There is a wide diversity of synaptic adhesion molecules

and here we discuss only those that have been identified at the

crossroads of 5-HT-dependent synaptic plasticity and the path-

ogenesis of neurodevelopmental disorders. These include integ-

rins, immunoglobulin superfamily (e.g., neural cell adhesion

Reviewmolecules, NCAMs), cadherins (CDHs), adhesion G protein-

coupled receptors (adhesion-GPCR; e.g., latrophilins, LPHNs),

leucine-rich repeat transmembrane proteins (e.g., LRRTMs,

FLRTs), neurexins (NRXNs) ,and neuroligins (NLGNs) (de Wit

et al., 2009; OSullivan et al., 2012; Sudhof, 2008; Williamset al., 2010a, 2011; Figure 5). A diversity of synaptic adhesion

molecules, including, e.g., NCAM1, NRXN1 and 3, CDH8, 11,

and 13, LPHN1 and 3, are expressed by serotonergic neurons

and some are subject to transcriptional regulation during the

process of synapse formation and remodeling (Bethea and

Reddy, 2012a, 2012b; Lesch et al., 2012b; Rivero et al., 2012;

Wylie et al., 2010).

Adhesion molecules modulate synapse formation by speci-

fying the connectivity between matched populations of neurons.

Once the synaptic partner is identified, the initial axo-dendritic

contact is transformed into a functional synapse by the recruit-

ment of other pre- and postsynaptic components. A well-char-

acterized mediator of synaptogenesis is the transsynaptic

NRXN-NLGN complex, in which presynaptic NRXNs interact

with postsynaptic NLGNs to bidirectionally specify synapses

(Sudhof, 2008). Although all neurons express NRXNs and

NLGNs, alternate promoter usage and extensive alternative

splicing of extracellular domain generates numerous different

isoforms of NRXNs likely confering specificity for glutamatergic

versus GABAergic synapse formation. Although NRXNs,

NLGNs, and LPHNs are structurally distinct, they display hetero-

philic interaction between their extracellular domains (Boucard

et al., 2012). By specifying synaptic functions, multiple parallel

transsynaptic signaling complexes shape unique network prop-

erties (Benson et al., 2000; Bockaert et al., 2010).

Synaptic adhesion molecules share the ability to trigger

multiple intracellular signaling cascades with metabotropic

5-HT and glutamate receptors as well as neurotrophin receptors

(Figure 5). The cytoplasmic domain of both NRXNs and NLGNs

contains PDZ-binding motifs that recruit messenger molecules

thought to mediate differentiation of the presynaptic and the

postsynaptic compartment, respectively. Several intracellular

signaling pathways may be activated by LPHNs via both Ca2+-

dependent and -independent mechanisms. The Ca2+-indepen-

dent effects are likely transduced by G proteins that trigger acti-

vation of both PLC and inositol-3-phosphate (IP3), resulting

in Ca2+ mobilization from intracellular Ca2+ stores, eventually

followed by release of neurotransmitters. Moreover, LPHNs

C-terminal regions interact with proteins of the SHANK family

(Kreienkamp et al., 2000), multidomain scaffold proteins of the

postsynaptic density that connect neurotransmitter receptors,

ion channels, and other membrane proteins to the actin cyto-

skeleton and G protein-coupled signaling pathways and also

play a role in synapse formation and dendritic spine maturation

(Holtmaat and Svoboda, 2009).

At the glutamatergic postsynapse, SHANKs couple to the

NMDARPSD-95nitric oxide synthase-1 (NOS1) complex via

interaction with the GKAP adaptor protein (Naisbitt et al., 1999;

Romorini et al., 2004). While GKAP is thought to be a PSD-95

associated scaffolding protein maintaining synaptic junctions

and synaptic stability, the PSD complex also operates as a func-

tional link as it tightly couples the NMDA receptor to NOS1. The

latter is able to bind to PSD-95 by a unique PDZ-PDZ domaininteraction, allowing for attachment of NOS1 to the NMDA

receptor complex. NOS1, which has also been reported to recip-

rocally interact with 5-HTT function (Chanrion et al., 2007), is

spatially close to where Ca2+ influx occurs, which activates

NOS1. Lastly, SHANKs bind to HOMER proteins, another group


Glutamate

MINT-1 Ca2+channel

PI3KERK1/2AKTGSK3mTOR

mGLUR5

Ribosome

F-actin

NMDAR

PSD-95

NLG

N

SHANK GKAP

HOMER

RhoA/ROCKRAC1

VELICASK

MTRRL

NOS1

PKC

PTENPSD-95MPP3

CaMK

IP3

[Ca2+]Synapticproteins

SAP-97

NXRN

NLG

N

mGLUR75-HT1B

5-HT2A/2C

Serotonin

NXRN

AMPAR5-HTT

DAG

5-HT1BP11

F-actin

Ribosome

Ribosome

AC

PKC

cAMP

PLCIP3

[Ca2+]DAG

Gq

FGFRNCAMPLC

F-actin

PICK1

PKASynapticproteins

Gi

PKA

GIRK2

PKA

GSK3

( e.g. glutamate,GABA, dopamine,acetylcholine )

5-HT1A

PI3KERK1/2AKTGSK3mTOR

CDH

Spine volume

PSD

size

N

MD

AR/

AM

PAR

ratio LTP

LTD

Synapticproteins

NHPL

5-HT1A

Figure 5. Prototypical Glutamatergic Synapse Modulated by Serotonergic InputThe model character of this hypothetical synapse allows depiction of multiple receptors and their postreceptor signal transduction, transsynaptic interactionsof adhesion molecules, and related intracellular signaling pathways regulating synaptic plasticity in a single schematic representation. For simplificationpurposes only a fraction of 5-HT receptor subtypes is depicted. Somatodendritic (5-HT1A) and terminal autoreceptors (5-HT1B) induce hyperpolarization thatdecreases the firing rate of 5-HT neurons. 5-HT2A and 5-HT2C basically activate phospholipase C (PLC) via the Gq protein but also impact a wide range ofdistinct signal transduction pathways by associating with multiple GPCR interacting proteins. The 5-HT2C stimulates the phosphoinositol second messengercascade which, in turn, stimulates the activation of protein kinase C (PKC) and opens L-type Ca2+ channels. The protein phosphatase and tensin homolog(PTEN) binds to the 5-HT2C receptor which also interacts with several proteins, such as postsynaptic density (PSD) proteins containing PSD-95-disc large-zonula occludens (PDZ) domains. Association of 5-HT2C receptors with PDZ domain-containing proteins affects both receptor desensitization and inter-nalization, depending on the type of the PDZ protein associated with the receptor. Neurexins (NRXNs) and their postsynaptic binding partners neuroligins(NLGNs), leucine-rich repeat transmembrane proteins (e.g., LRRTMs, FLRTs) and adhesion G protein-coupled receptors (adhesion-GPCR; e.g., latrophilins,LPHNs). Other synaptic adhesion proteins are members of the immunoglobulin superfamily (e.g., neural cell adhesion molecules, NCAMs) or cadherin family(e.g., CDH9, atypical CDH13). NRXNs interact with the scaffolding molecule CASK and NLGNs interact with the scaffolding molecule PSD-95 or SAP-97,which binds NMDA and AMPA receptors (NMDAR and AMPAR) via their PDZ domain. Alternatively spliced NRXNs bind the postsynaptic adhesion moleculeLRRTM2, which can recruit NMDARs and AMPARs. NCAMs interact with the fibroblast growth factor receptor (FGFR) signaling (PI3K, ERK, AKT, GSK3,mTOR) pathway, which is also activated by CDHs. Several intracellular signaling pathways may be activated by LPHNs including Ca2+-dependent and-independent mechanisms. Moreover, LPHNs C-terminal region interacts with proteins of the SHANK family. SHANK proteins are synaptic multidomain PSDscaffold proteins binding to HOMER proteins, another group of postsynaptic density scaffolding proteins, which, in turn, are able to interact with mGLUR5.SHANK and HOMER proteins cross-link mGLURs with LPHNs. 5-HT1A activation decreases NMDA receptor-mediated currents in PFC pyramidal neuronsthrough reduction of ERK1/2 activity, which leads to a decrease in microtubule-associated protein-2 (MAP2) phosphorylation, MAP2-microtubule interactionand microtubules stability involved in clustering the NMDA 2B subunit. In contrast, 5-HT2A/2C activation increases NMDA receptor-mediated currents byactivating the ERK1/2 pathway, thus counteracting the effects of 5-HT1A activation in decreasing NMDA receptor-mediated currents. Metabotropic glutamatereceptors (e.g., mGluR5, mGluR7) stimulate protein kinase A (PKA) and PKC pathways. mGluR5 not only interacts with signaling of 5-HT receptors but alsowith NMDA receptors resulting in reciprocal and agonist-independent inhibition of the two receptors. P11 and GSK3 may directly interact with 5-HT1B,

182 Neuron 76, October 4, 2012 2012 Elsevier Inc.

Neuron

Review

roaohehetr

Neuron

Reviewof postsynaptic density scaffolding proteins (Tu et al., 1999; Xiao

et al., 2000), which, in turn, are able to interact with mGluR1 and

nuclei to various association cortices, while physiological responses can be pthe hypothalamus and brainstem. Excessive or insufficient activation of thesensitivity to social signals. The orbitofrontal cortex, through its connectionswithin limiting emotional outbursts, and the anterior cingulate cortex recruits otenvironmental factors contribute to the structure and function of this circuitry, tassociate stimuli with events that are either punishing or rewarding. vmPFC, venarea; LC, locus ceruleus.mGluR5. SHANK and HOMER proteins can cross-link mGluRs

with LPHN3, which hence, in addition to its interaction with

FLRT3 and subsequent G protein signaling, impacts glutamater-

gic transmission in a dual mode (OSullivan et al., 2012). The

signaling pathway activating interaction of synaptic adhesion

molecules ultimately converges on the machinery regulating

gene transcription which, in turn, results in de novo synthesis

of structural and functional synaptic proteins by local ribosomes.

Serotonin-Induced Modulation of Adhesion MoleculesFacilitates Remodeling of Synapses in EmotionalLearningAs a prototypical network subject to 5-HT-induced modulation,

the circuitry of experience-dependent associative and emotional

learning has been implicated in social cognition and emotion,

including the associated phenomena of contextual fear re-

sponses (Figure 6; LeDoux, 2012). While a complex develop-

mental program encodes the formation and function of this

circuitry, the amygdala governs essential processes ranging

from cognition to emotion, to learning and memory (Phelps,

2006). While genetic variation and environmental factors

contribute to the structure and function of this circuitry, the

amygdala-associated network is centrally involved in processes

of learning to associate stimuli with events that are either punish-

ing or rewarding, commonly referred to as emotional learning.

whereas PTEN, MPP3, and PSD-95 are able to bind to 5-HT2C. Long-term potePSD size, and NMDR/AMPAR ratio are synaptic plasticity events that increase orLTP requires increased gene transcription and de novo synthesis of structurasupport the molecular basis of learning and memory.The recognition of the amygdala as an essential neural substrate

for acquisition and expression of learned fear has permitted

Figure 6. Serotonin and the Neurocircuitryof Emotional LearningModified from Lesch (2007). A network of inter-connected structures modulated by the median(MR) and dorsal (DR) raphe 5-HT system has beenimplicated in emotion learning, specifically fearresponse. Fear-related circuits involve pathwaystransmitting information to and from the amygdalato various neural networks that control theexpression of avoidant, defensive, or aggressivereactions, including behavioral, autonomic, andstress hormone responses. While pathways fromthe thalamus and cortex (sensory and prefrontal)project to the amygdala, inputs are processedwithin intra-amygdalar circuitries and outputs aredirected to the hippocampus, brain stem, hypo-thalamus, and other regions. Perception of dangeror threat and other social cues are transmittedto the lateral nucleus of the amygdala, whichprojects to the basal nuclei where informationregarding the social context derived from orbito-frontal projections is integrated with the percep-tual information. Behavioral responses can then beinitiated via activation of projections from the basal

duced via projections from the basal nuclei to the central nucleus and then tomygdala leads to either disproportionate negative emotionality or impairedther domains of the prefrontal cortex andwith the amygdala, plays a critical roler entities during incremental levels of arousal. While genetic variation andamygdala-associated network is centrally involved in processes of learning toomedial prefrontal cortex; SSC, somatosensory cortex; VTA, ventral tegmentalelectrophysiological characterization of synaptic processes in

the amygdala that mediate fear conditioning. Although the

mechanisms underlying the induction and expression of LTP in

the amygdala are only beginning to be understood, LTP induces

postsynaptic GluR1 delivery in amygdala in conjunction with

modified presynaptic plasticity in the lateral nucleus (Maren,

2005; Rumpel et al., 2005). Reduction of NLGN-1 expression in

pyramidal neurons of the lateral amygdala decreases NMDAR-

dependent postsynaptic currents, impairing LTP at thalamo-

amygdalar synapses, and triggers deficits in conditioned fear

memory storage, consistent with the requirement of NMDA

receptor activation for expression of synaptic plasticity in mature

neural circuits in the amygdala (Kim et al., 2008).

An impact of 5-HT on NRXN and NLGN function at sensory-to-

motor neuron synapses of the gill-withdrawal reflex in Aplysia,

which exhibits sensitization, named long-term facilitation (LTF),

as a basic mechanism of conditioned fear response, was

recently demonstrated (Choi et al., 2011). LTF is induced through

5-HT receptor-mediated activation of cAMP-dependent PKA

or PKC. These effectors subsequently recruit the mitogen-

activated kinase (MAPK) signaling pathway which in turn initiates

transcription factor CREB-dependent modulation of transcrip-

tional activity. Suppression of NRXN in the presynaptic sensory

neuron or NLGN in the postsynaptic motor neuron eliminates

both LTF and the associated presynaptic growth provoked by

ntiation (LTP) and long-term depression (LTD) as a function of spine volume,decrease the strength of synaptic transmission for long periods, respectively.l and functional synaptic proteins by local ribosomes which are believed to


Neuronrepetitive application of 5-HT. Moreover, introduction of an

autism-linked NLGN-3 mutation into the postsynaptic motor

neuron decreases transsynaptic signaling efficiency reflected

by obliteration of LTF. The maintenance of LTF and synaptic

growth requires ribosome-mediated synaptic protein synthesis

and is dependent on the translational regulator, cytoplasmic pol-

yadenylation element-binding protein (CPEB) (Miniaci et al.,

2008; Si et al., 2003). The findings further support the notion

that 5-HT-induced recruitment of NRXNs and NLGNs partici-

pates in the different stages of emotional memory formation

and to learning-related structural remodeling that results in an

expansion of synaptic connections and increase in signaling effi-

ciency associated with storage of long-term memory, including

emotional memory. Thus, 5-HT-evoked moderation of activity-

dependent regulation of NRXN-NLGN interaction likely governs

transsynaptic signaling required for the cognitive and emotional

processes that are impaired in neurodevelopmental disorder.

Serotonin-Moderated Epigenetic Programming ImpactsSynaptic PlasticityEnvironmental adversity and early-life stress experience during

gestation and the postnatal period are associated with increased

risk for neurodevelopmental disorders and psychiatric condi-

tions later in life. A considerable number of human and animal

model studies indicate that the impact of gene-by-environment

interaction on brain development and functionspecifically in

the domain of social cognition and emotional learningis

moderated by 5-HT (for review, Homberg and Lesch, 2011;

Lesch, 2011). The molecular mechanisms by which environ-

mental adversity impacts processing social cues and resulting

emotional responses are not known, but are likely to include

epigenetic programming of gene expression (Bartolomucci

et al., 2010; Carola et al., 2008; van den Hove et al., 2011). In

addition to its direct role in the regulation of gene transcription

via receptor-mediated intracellular signaling-dependent activa-

tion or inhibition of transcription factors, 5-HT also modulates

synaptic plasticity by influencing epigenetic modification (DNA

methylation, histone modifications) of genomic regions contain-

ing transcription factors and through microRNA (miRNA)-facili-

tated transcriptional repression via 5-HT receptor-mediated

activation of intracellular signaling pathways converging on the

transcriptional machinery of specific genes (e.g., Baudry et al.,

2010; Figure 7). Epigenetic modification was therefore sug-

gested as a potential mechanism for stabilizing gene expression

that leads to persisting changes in the functional state of neurons

required for long-term memory storage.

miRNAs, a subclass of small RNA regulators that are involved

in numerous cellular processes, including proliferation, differen-

tiation, and plasticity (Krol et al., 2010; Millan, 2011), contribute

to transcriptional and epigenetic regulation of gene expression

during brain development and in differentiated neurons (Qureshi

and Mehler, 2012; Saba and Schratt, 2010). Brain-specific miR-

NAs constrain 5-HT-induced synaptic LTF through repression ofthe transcriptional activator CREB1 (Rajasethupathy et al.,

2009). It has also recently been reported that another class of

small noncoding regulatory RNAs, PIWI-interacting RNAs

(piRNAs), are enriched in neurons of Aplysia and mouse and

may have a role in spine morphogenesis (Lee et al., 2011; Raja-

184 Neuron 76, October 4, 2012 2012 Elsevier Inc.sethupathy et al., 2012). Expression of several piRNAs is induced

by 5-HT and PIWI/piRNA complexes moderate 5-HT-dependent

methylation of CpG sites in the promoter of target genes, such as

the plasticity-related transcriptional repressor CREB2. Together,

these findings outline a small RNA-mediated gene regulatory

mechanism for enhancing or constraining 5-HT-dependent

LTF/LTP thus establishing enduring adjustments in mature

neurons for the long-term encoding of memory and its cogni-

tive-emotional reappraisal.

Serotonin-Glutamate Interactionin Neurodevelopmental DisordersNeurodevelopmental disorders are generally characterized by

severe impairments in the domains of attention, motivation,

cognition, and emotion, display remarkable syndromal overlap,

and persist across the life span. Multiple lines of evidence impli-

cate serotonergic and glutamatergic pathway malfunction

particularly in autism spectrum disorder (ASD), which is charac-

terized by deficits in social cognition, communicative interaction,

and emotional learning as well as by patterns of repetitive,

restricted behaviors or interests and resistance to change (Du-

rand et al., 2007; Grabrucker et al., 2011; Moessner et al., 2007).

The role of 5-HT in ASD has been investigated with genetic,

neuroimaging and biomarker approaches (for review, Pardo

and Eberhart, 2007). Neuroimaging revealed that the peak in

brain 5-HT synthesis capacity seen in typically developing

infants at 2 years of age is absent in children with autism (Chan-

dana et al., 2005). Reduction of 5-HT in dentatothalamocortical

pathways, with simultaneous increases in the contralateral den-

tate cerebellar nucleus as well as reduced 5-HT2A receptor

binding in the cortical areas was reported (Murphy et al.,

2006). These changes may reflect compromised formation of

the 5-HT system with an increased number but dysmorphic

manifestation of serotonin axons in terminal regions of the cortex

(Azmitia et al., 2011). Moreover, elevated levels of 5-HT and

decreased 5-HT2 receptor binding in the platelets have also

been observed (Cook and Leventhal, 1996). Genetic studies

have identified variants in 5-HT system-related genes, including

5-HTT/SLC6A4 which also shows association with cortical gray

matter volume and interaction with PTEN and neurotrophins,

such as brain-derived neurotrophic factor (BDNF) (Page et al.,

2009; Ren-Patterson et al., 2006; Ren-Patterson et al., 2005).

Finally, pharmacological interventions with compounds acting

on 5-HT2 receptors and SSRIs are effective in improving social

cognition and interaction while decreasing aggressive and

stereotyped behaviors in children with ASD (Cook and Leven-

thal, 1996). Together, 5-HT system dysregulation coinciding

with abnormalities in the glutamatergic pathway and their impact

on brain development and plasticity supports a critical role of

5-HT-glutamate interaction in the etiopathogenesis of autism

and related disorders.

Neurodevelopmental disorders display a complex genetic

architecture where multiple common and rare genetic variants

Reviewin interaction with environmental adversity contribute to risk.

There is now replicated evidence that rare chromosomal dupli-

cations and deletions known as copy-number variants (CNVs)

are associated with ASD risk (for review, Abrahams and Gesch-

wind, 2008; Devlin and Scherer, 2012) and that the chromosomal

an

NeuronTr

Transcriptional regulation

Transcription factors

Structural &

functional proteins Epigenetic

regulators

piRNAs

Reviewregions spanned by these CNVs show significant overlap

with those implicated in attention-deficit/hyperactivity disorder

(ADHD) and schizophrenia (Elia et al., 2012; Lesch et al., 2011;

Lionel et al., 2011; Malhotra and Sebat, 2012; Talkowski et al.,

2012; Williams et al., 2010b, 2012). Thus, it came as no surprise

that these genome-wide analyses revealed risk genes encod-

ing synaptic adhesion molecules (e.g., CDHs, NLGNs, NRXNs,

and LPHNs), glutamate receptors (e.g., NMDARs, mGluRs) and

their mediators of intracellular signaling pathways, as well as

components of the PSD and activity-regulated cytoskeleton-

associated protein complexes (e.g., SHANKs). In ASD, CNV

screening and deep sequencing are rapidly identifying genes

for further characterization. These approaches have implicated,

among others, CDH810, CDH13, NLGN3, NLGN4, SHANK13,

NRXN1,NRXN3, ASTN2,DPP6, andCNTNAP2 as affecting ASD

risk (Devlin and Scherer, 2012; Pagnamenta et al., 2011; Sanders

et al., 2011; Singh et al., 2010; Wang et al., 2009). Some rare,

highly penetrant mutations appear to be monogenic causes of

ASD. Moreover, large-scale whole-exome sequencing is

currently identifying numerous rare single nucleotide variants

mRNA

Epigenetic pattern DNA Methylation

Me

Ac Histone modifications

Figure 7. Regulatory Circuits of Gene ExpressionEpigenetic mechanisms including DNA methylation and histone modifications afraction of small noncoding regulatory RNAs, regulate gene expression patternepigenetic modifications and miRNAs control each other to form regulatory circregulation of the transcriptional machinery via receptor-mediated intracellular smodulates synaptic plasticity by influencing epigenetic patterns of genomic regrepression via 5-HT receptor-mediated activation of intracellular signaling pathwscription

+

- Posttranscriptional

repression

Epigenetically regulated microRNAs (SNVs) potentially be associated with de novo and inherited

ASD (Neale et al., 2012; ORoak et al., 2012; Sanders et al.,

2012).

Since individuals with severe disorders particularly of the

autism or schizophrenia spectrum may have developed as ex-

pected but at a certain stage present with indicators of regres-

sion in cognitive, emotional, and psychosocial capacities,

neurodevelopmental disorders may not arise from a deleterious

impact on initial synapse formation but rather on synaptic re-

modeling in the course of the brains maturation and subsequent

consolidation processes of circuit connectivity. The core symp-

toms of neurodevelopmental disorders likely arise from a defi-

ciency in the multifaceted crosstalk among numerous synaptic

adhesion molecules, both at the extracellular level and at the

level of their intracellular signaling pathways.

Based on the contribution of adhesion molecules to synaptic

remodeling and circuit maturation in neurodevelopmental dis-

orders, the contribution of NRXNs and NLGNs to cognitive

function and synaptic plasticity was also studied in genetically

modified mouse models. Mice constitutively deficient for Nlgn1

mRNA cleavage

Translational repression

Deadenylation microRNAs

s well as microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), anothers at both the transcriptional and posttranscriptional level. At the same time,uits and to maintain physiological functions. In addition of its direct role in theignaling-dependent activation or inhibition of transcription factors, 5-HT alsoions containing transcription factors or by miRNAs-facilitated transcriptionalays converging on the transcriptional machinery of specific genes.


Neuronrevealed that NGLNs are essential for lateral trafficking of

NMDA receptors to postsynaptic site and maintaining NMDA

receptor-mediated currents, whereas a humanized mouse

model with a knockin of a NLGN3 mutation was reported to

display autism-related behavioral abnormalities (Tabuchi et al.,

2007). In contrast, Nrxn-1a knockout mice exhibit enhanced

motor learning capacities, despite deficient glutamatergic

transmission (Etherton et al., 2009). Together, Nrxn and Nlgn

inactivation fails to change synapse number, suggesting that

both moderate synaptic remodeling and maturation rather

than initial synapse formation. In support of a contribution of

adhesion molecules to the activity-dependent modification of

developing neural circuits, in vitro approaches revealed that

inhibition of NMDA receptors suppresses the synaptogenic

activity of NLGN1 (Chubykin et al., 2007). Mutations in SHANK3

(Durand et al., 2007; Grabrucker et al., 2011; Moessner et al.,

2007) are thought to result in modifications of dendritic spine

morphology via an actin-dependent mechanism (Durand et al.,

2012), likely to result in defects at striatal synapses and cortico-

striatal circuits that were reported in Shank3 mutant mice (Peca

et al., 2011).

Linking 5-HT Receptor-mGluR Crosstalk to Defectsin Synaptic PlasticityTranssynaptic signaling mediated by mGluR5 modulates effi-

ciency and timing of excitatory transmission in a behaviorally

relevant manner. Group I, II, and III mGluRmembers are required

for different modes of pre- and postsynaptic short- and long-

term plasticity. Given the target-specific distribution of mGluRs,

such that synaptic input from one presynaptic neuron is modu-

lated by different receptors at each of its postsynaptic targets,

mGluRs provide a mechanism for synaptic specialization of glu-

tamatergic transmission. Interactions between 5-HT receptors

and mGluRs have also been identified. For example, mGluR2

interacts through specific transmembrane helix domains with

the 5-HT1A receptor to form functional complexes in cortex,

thus triggering cellular responses in disorders of cognitive pro-

cessing and in response to pharmacological intervention

(Gonzalez-Maeso et al., 2008).

Although mGluR5 was previously implicated in neurodevelop-

mental disorders (Auerbach et al., 2011; Devon et al., 2001;

Schumann et al., 2008; Wang et al., 2010), a recent genome-

wide screen showed that the GRM gene family encoding

mGluRs, most frequently GRM5, and genes interacting with it

are enriched for CNVs in ADHD (Elia et al., 2012; Lesch et al.,

2012b). ADHD is characterized by developmentally inappro-

priate inattention, hyperactivity, increased impulsivity and emo-

tional dysregulation with a specific constellation of deficits in

motivation, working memory and cognitive control of executive

functions, thus displaying syndromal overlap with ASD. Other

CNV findings concerned GRM1 duplications, GRM7 deletions,

and GRM8 deletions. Overall the findings indicate that up to

10% of individuals with ADHD may be enriched for mGluRnetwork variants. Several of these genes play a central role in

the process of neurogenesis, synaptic transmission and network

connectivity that has been argued to be defective in ADHD.

Specifically, mGluRs modulate mRNA generation, alternative

splicing and translation, processes known to influence

186 Neuron 76, October 4, 2012 2012 Elsevier Inc.circuitry-specific formation, activity and plasticity of synapses

(Bockaert et al., 2010; Knafo and Esteban, 2012).

Disruption of frontostriatal circuitries which are involved in

motor control and action learning, is thought to represent a

specific characteristic of ADHD pathophysiology (Cubillo et al.,

2012; de Zeeuw et al., 2012). Enhanced short-range connectivity

within motivation-reward networks and their decreased connec-

tivity with structures comprising the default-mode and dorsal

attention networks have been reported, indicating impaired

crosstalk among cognitive control and reward pathways that

may reflect attentional andmotivational deficits in ADHD (Tomasi

and Volkow, 2012; Volkow et al., 2012). Since it is abundantly ex-

pressed in dendritic spines of structural units of the frontostriatal

circuit including nucleus accumbens, dorsal striatum and PFC,

mGluR5 not only interacts with signaling of dopamine and

5-HT receptors but also with NMDA receptors, resulting in recip-

rocal and agonist-independent inhibition of the two receptors

(Perroy et al., 2008). While mGluR5 is confined to the periphery

of the synapse, NMDA receptors are located vis-a`-vis of the

glutamate release site in the PSD comprising the multiprotein

HOMER-SHANK-GKAP-PSD-95 scaffolding complex physically

and functionally linking the two receptors (Fagni et al., 2008).

Moreover, the nucleus accumbens and dorsal striatum receive

extensive serotonergic input mediated by a multitude of 5-HT

receptors including subtypes 5-HT1-4 (Figure 2). 5-HT activates

5-HT1B receptors resulting in a cAMP-dependent LTD-associ-

ated decrease of glutamate release and striatal output (Mathur

et al., 2011; Navailles and De Deurwaerdere, 2011). This 5-HT-

induced LTD is independent of dopamine, suggesting that sero-

tonergic and dopaminergic signaling pathways both interact in

corticostriatal circuit plasticity. In line with these presumed

molecular mechanisms, both pharmacological inhibition of

mGlurR5 or targeted inactivation of its gene Grm5 result in loco-

motor hyperactivity and reduced habituation to novelty (Halber-

stadt et al., 2011; Kachroo et al., 2005). Deficits in spatial learning

as well as acquisition and retrieval of stimulus-outcome memo-

ries in a fear conditioning paradigm have also been reported

(Jia et al., 2001; Xu et al., 2009). Electrophysiological studies in

Grm5 knockout mice revealed sensorimotor gating deficits sug-

gesting a key role for this gene in the modulation of hippocampal

NMDA receptor-dependent synaptic plasticity (Jia et al., 1998).

Dissection and characterization of the molecular components

of these transsynaptic signaling interfaces and their involvement

in the modulatory action of 5-HT on synaptic plasticity is likely to

give better insight into the pathogenesis of neurodevelopmental

disorders and to provide novel targets for translation into inter-

ventional strategies.

Conclusion and OutlookOur understanding of how 5-HT-dependent modulation of circuit

configuration influences social cognition and emotional learning

has been enhanced by recent insight into the molecular

machinery that connects pre- and postsynaptic neurons and

Reviewthe cellular mechanisms of synapse formation and plasticity.

However, we have made only the first few steps on the long

and winding road toward an understanding of the neural mech-

anisms underlying cognition-emotion continuum as the funda-

mental basis of effective social functioning (Pessoa, 2008), and

toric population expansion andmigration, agricultural revolution,

Neuronindustrialization, and urbanization of life styles (Lupski et al.,

2011; McClellan and King, 2010), which complements the

evidence for a link between neural plasticity and the multidimen-

sional cognitive and emotional processes of decision-making

(Canli and Lesch, 2007; Frith and Singer, 2008; Steinbeis et al.,

2012). Although the fusion of humanities, social sciences and

neurosciences is under way, the transition from complex corre-

lations and interactions to applicable prediction is the genuine

challenge.

ACKNOWLEDGMENTS

We apologize to colleagues whose work could not be cited due to spacelimitations. The writing of this article and the authors related research weresupported by the Deutsche Forschungsgemeinschaft (SFB 581/B9, SFBTRR 58/A1 and A5, KFO 125). The authors thank J. Stilla and G. Lesch forassistance in generating graphical material. The authors are also grateful toC. Gross for his critical comments.

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